Addiction and the adrenal cortex

Substantial evidence shows that the hypophyseal–pituitary–adrenal (HPA) axis and corticosteroids are involved in the process of addiction to a variety of agents, and the adrenal cortex has a key role. In general, plasma concentrations of cortisol (or corticosterone in rats or mice) increase on drug withdrawal in a manner that suggests correlation with the behavioural and symptomatic sequelae both in man and in experimental animals. Corticosteroid levels fall back to normal values in resumption of drug intake. The possible interactions between brain corticotrophin releasing hormone (CRH) and proopiomelanocortin (POMC) products and the systemic HPA, and additionally with the local CRH–POMC system in the adrenal gland itself, are complex. Nevertheless, the evidence increasingly suggests that all may be interlinked and that CRH in the brain and brain POMC products interact with the blood-borne HPA directly or indirectly. Corticosteroids themselves are known to affect mood profoundly and may themselves be addictive. Additionally, there is a heightened susceptibility for addicted subjects to relapse in conditions that are associated with change in HPA activity, such as in stress, or at different times of the day. Recent studies give compelling evidence that a significant part of the array of addictive symptoms is directly attributable to the secretory activity of the adrenal cortex and the actions of corticosteroids. Additionally, sex differences in addiction may also be attributable to adrenocortical function: in humans, males may be protected through higher secretion of DHEA (and DHEAS), and in rats, females may be more susceptible because of higher corticosterone secretion.

THROMBOTIC MICROANGIOPATHY IN HAEMATOPOIETIC CELL TRANSPLANTATION:AN UPDATE

Allogeneic hematopoietic cell transplantation (HCT) represents a vital procedure for patients with various hematologic conditions. Despite advances in the field, HCT carries significant morbidity and mortality. A rare but potentially devastating complication is transplantation-associated thrombotic microangiopathy (TA-TMA). In contrast to idiopathic TTP, whose etiology is attributed to deficient activity of ADAMTS13, (a member of the A Disintegrin And Metalloprotease with Thrombospondin 1 repeats family of metalloproteases), patients with TA-TMA have > 5% ADAMTS13 activity. Pathophysiologic mechanisms associated with TA-TMA, include loss of endothelial cell integrity induced by intensive conditioning regimens, immunosuppressive therapy, irradiation, infections and graft-versus-host (GVHD) disease. The reported incidence of TA-TMA ranges from 0.5% to 75%, reflecting the difficulty of accurate diagnosis in these patients. Two different groups have proposed consensus definitions for TA-TMA, yet they fail to distinguish the primary syndrome from secondary causes such as infections or medication exposure. Despite treatment, mortality rate in TA-TMA ranges between 60% to 90%. The treatment strategies for TA-TMA remain challenging. Calcineurin inhibitors should be discontinued and replaced with alternative immunosuppressive agents. Daclizumab, a humanized monoclonal anti-CD25 antibody, has shown promising results in the treatment of TA-TMA. Rituximab or the addition of defibrotide, have been reported to induce remission in this patient population. In general, plasma exchange is not recommended.

Placental restriction alters circulating thyroid hormone in the young lamb postnatally

Intrauterine growth restriction (IUGR) is associated with accelerated growth and increased adiposity in early life due to unknown mechanisms, which could include increased thyroid hormone (TH) action. We hypothesized that placental restriction (PR) of fetal growth would increase circulating TH concentrations and alter their response to fasting, and that these would relate to growth and body composition in the young lamb. PR reduced size at birth, increased fractional growth rates (FGRs) of soft and skeletal tissues up to 30 days of age, and slowed the ontogenic decrease in plasma total T3 and plasma total T3/T4. PR did not alter the abundance of plasma THs after short-term fasting. In general, plasma total T3 and total T3/T4 ratio correlated negatively, whereas plasma total T4 correlated positively with size at birth. Absolute growth rates of weight and crown-rump length correlated positively with plasma total T3 and total T4 between days 15 and 35. Current FGRs for weight and metatarsal length correlated positively with plasma total T3 between days 20 and 35. In conclusion, PR and small size at birth reduce plasma total T4 and increase plasma total T3 postnatally, whereas catch-up growth relates to increased abundance of the more bioactive forms of TH. Finally, greater soft tissue growth occurs in PR compared with control lambs at the same circulating TH concentrations. This suggests that PR and small size at birth may increase activation of T4 to T3 and sensitivity of soft tissues to TH, which may contribute to catch-up growth following IUGR.

Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue

Pharmacological manipulation of brain serotonergic [5-hydroxytryptamine (5-HT)] activity affects run time to exhaustion in the rat. These effects may be mediated by neurochemical, hormonal, or substrate mechanisms. Groups of rats were decapitated during rest, after 1 h of treadmill running (20 m/min, 5% grade), and at exhaustion. Immediately before exercise rats were injected intraperitoneally with 1 mg/kg of quipazine dimaleate (QD; a 5-HT agonist), 1.5 mg/kg of LY 53857 (LY; a 5-HT antagonist), or the vehicle (V; 0.9% saline). LY increased and QD decreased time to exhaustion (approximately 28 and 32%, respectively; P < 0.05). At fatigue, QD animals had greater plasma glucose, liver glycogen, and muscle glycogen concentrations but lower plasma free fatty acid concentration than did V and LY animals (P < 0.05). In general, plasma corticosterone and catecholamine levels during exercise in QD and LY rats were similar to those in V rats. Brain 5-HT and 5-hydroxyindole-3-acetic acid concentrations were higher at 1 h of exercise than at rest (P < 0.05), and the latter increased even further at fatigue in the midbrain and striatum (P < 0.05). Brain dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were higher at 1 h of exercise (P < 0.05) but were similar to resting levels at fatigue. QD appeared to block the increase in DA and DOPAC at 1 h of exercise, and LY prevented the decrease in DA and DOPAC at fatigue (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

EFFECT OF AGE AND SEX ON THE PLATELET FATTY ACID (FA) COMPOSITION AND IN ITS MODULATION BY PLASMA FA

Age, sex and platelet hyperactivity are factors that condition the development of coronary heart disease (CHD). Platelet function is believed to be influenced by its FA pattern, which can be modulated by the FA composition of plasma lipid fractions. Therefore, it seemed of interest to evaluate the effect of age and sex on platelet FA and ascertain whether the plasma influence on platelet FA is modified by age and sex. The study has been performed in 98 subjects, 49 couples, men (M) and women (W), living together and with the same dietary habits. The subjects were divided into three age groups : G I:16-40, GII:40-60,and G III: 60. Plasma and platelet FA of phospholipids (PL), triglycerides, and free FA fractions were evaluated by gas-chromatography. The results showed scarce differences in platelet FA in relation to sex. With respect to age, the percentages of 18:2 and 20:5 in most platelet lipid fractions both in M and in W decrease with age. More interesting are the differences in correlation found between plasma and platelet FA, particularly in the PL fraction, with age and sex. In this respect an increase in the correlation coefficient was found for 16:0,18:0 and 20:4 and a decrease for 20:5 in middle aged men and postmenopausic women (Table). The similarity between these two groups of subjects may have a physiopathological meaning, if we take into account that both are more susceptible to CHD and that an increase in 16:0, 18:0 and 20:4 as well as a decrease in 20:5 may condition a platelet hyperfuntion, circumstance that may be more easily produced by plasma influence in those subjects.The results of the present study also confirm that that in general plasma greately influences the platelet content in 18:1, 18:2 and to a lower extent the saturated FA.